One of the largest challenges in pharmaceutical drug development is that drug compounds very often are insoluble, or poorly soluble, in aqueous media. Insufficient drug solubility in turn means insufficient bioavailability and poor plasma exposure of the drug when administered to subjects such as humans and animals.
It is estimated that between 40% and 70% of all new chemical entities identified in drug discovery programs are insufficiently soluble in aqueous media (M. Lindenberg, S et al.: European Journal of Pharmaceutics and Biopharmaceuticals, vol. 58, no. 2, pp. 265-278, 2004; DJ. Houss: Drugs and Pharmaceutical Sciences, Vol. 170, pp. 1-339, Informa Healthcare NC, 2007).
Gupta et al.; Volume 2013, Article ID 848043 Review Article at dx.doi.org/10.1155/2013/848043 Scientists have investigated various ways of solving the problem with low drug solubility in order to enhance bioavailability of poorly absorbed drugs, aiming at increasing their clinical efficacy when administered orally. Technologies such as increase of the surface area and hence dissolution may sometimes solve solubility problems. Other techniques that may also solve bioavailability problems are addition of surfactants and polymers. However, each chemical compound has its own unique chemical and physical properties, and hence have its own different challenges when being formulated into a pharmaceutical drug that can exert its clinical efficacy.
Formulating a drug in different types of lipids are useful for particular drugs. Lipid formulations for oral administration generally consist of a drug dissolved in a blend of excipients with a wide variety of physicochemical properties ranging from pure triglyceride oils, mono- and diglycerides, and a substantial portion of lipophilic or hydrophilic surfactants and co-solvents.
The main considerations in selecting appropriate excipients for any lipid-based formulation is identifying one or more excipients which have the ability to solubilise the complete dose and which at the same time provides a formulated unit dosage of the drug that can be taken orally and being of a size that can be swallowed by the patient. Usually, the drug load in combination with the size of a tablet or capsule is a limitating factor.
Lipid-based formulations may contain one lipid only, or a mixture of different types of lipids in combination. It is also common that in formulating a poorly soluble drug, it is required to also include one or more additional excipients to obtain a satisfactory solublity as well as drug stability. Pharmaceutical formulations comprising several types of lipid systems in combinations often tend to be complicated to produce and hence the cost of goods increases.
Self-Emulsifying Drug Delivery Systems (SEDDS) may be useful to formulate poorly soluble drugs. However, very few lipid based formulations have reached the pharmaceutical market place. The edible oils which represent the logical and preferred lipid excipient choice for the development of SEDDS, are not frequently selected due to their poor ability to dissolve large amounts of lipophilic drugs. The self-emulsifiyng properties also require the incorporation of relatively large amounts of surfactant in the formulation in addition to the oily drug carrier vehicle.
A mixture of mono- and diglycerides of caprylic/capric acid (Akoline) is an emulsifyer of natural origin that is preferred since it is considered as more safe than synthetic commercially available surfactants. However, it is recognized among scientists in the pharmaceutical field that such excipients have limited self-emulsification efficiency (P. P. Constantinides; Pharmaceutical Research, vol. 12, no. 11. Pp. 1561-1572, 1995).
Usually, the surfactant concentration ranges between 30 and 60% of the total formulation in order to form SEDDS (C. W. Pouton; International Journal of Pharmaceutics, vol. 27, no. 2-3, pp. 335-348, 1985). Large amounts of surfactants may cause GI irritations. The surfactants involved in the formulation of SEDDS should have a relatively high HLB and hydrophilicity to enable rapid and facile dispersion in the aqueous GI fluid as a very fine oil-in-water emulsion, and hence good self-emulsifying performance can be achieved. Also, one or more co-solvents are often added to the formulation to assist in solubilising high concentrations of the drug.
The compound 3α-ethynyl-3β-hydroxyandrostan-17-one oxime is a compound currently in clinical Phase II for the treatment of Hepatic Encephalopathy (HE) and Hypersomnia (HS). One of the problems with this compound is that it has a poor solubility in aqueous media, and hence there is a need to find a way to formulate this compound in order to obtain a clinically and commercially feasible drug product.